July 2015, Special ASCO Edition

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Urine Assays Detect Early Mutations in Patients with Advanced Cancers

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An assay that measures circulating tumor DNA (ctDNA) in the urine can detect mutations in patients with advanced cancers.

In one study, tracking cell-free DNA mutations in the urine from patients with refractory cancers found that low-frequency KRAS mutations were present in about 80%, said Filip Janku, MD, PhD.

“We found some emerging data that even though BRAF and KRAS were deemed to be mutually exclusive, in some patients with BRAF mutations, you can actually find low-frequency clones of KRAS in the cell-free DNA, which might potentially reflect tumor heterogeneity and the resistant clones which might ultimately emerge because of selection pressure,” said Janku, Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston.

Of 34 patients with BRAF V600E mutations in the tumor, 32 (94%) also had detectable BRAF V600E mutations in the urine. In 25 of 34 patients (74%) analyzed longitudinally, changes in cell-free DNA BRAF V600E copies correlated with percentage changes in target lesions on imaging. “The number of patients with KRAS mutations goes up as well as the number of detected KRAS mutations,” he said.

Urinary cell-free DNA was able to detect acquisition of KRAS G12/13 mutations in patients treated with BRAF- or MEK-targeted therapy. Some patients without KRAS mutations detected before treatment had KRAS mutations emerge on treatment, said Janku.

Of the 31 patients tested for urinary KRAS G12/13 mutations, 25 (81%) had low-frequency KRAS G12/13 mutations on at least 1 test that were not detected in tumor samples by standard tissue technologies; 11 had detectable urinary KRAS mutations before treatment and 19 while on treatment.

“The next step, once we figure out how we can monitor the clonal evolution, is to test acting on the information in clinical trials,” said Janku.

In a second study, early acquisition of epidermal growth factor receptor (EGFR) resistance mutations in patients with metastatic lung adenocarcinoma was found by measuring ctDNA in the urine.

Acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) develops in most patients by 12 months. The secondary T790M mutation occurs in about 60% of patients with acquired resistance to EGFR TKIs, according to Hatim Husain, MD, Assistant Professor of Hematology-Oncology, Moores Cancer Center at the University of California, San Diego, and colleagues.

An EGFR T790M resistance mutation was detected in urinary ctDNA months before progression on anti-EGFR TKIs. The urine-based testing system extracts ctDNA from urine samples and uses polymerase chain reaction to amplify small DNA fragments while enriching for mutant alleles. The urine-based biopsy provides a noninvasive alternative to the tissue biopsy to detect T790M in relapsed patients.

Among 14 metastatic lung cancer patients with tissue-confirmed T790M, urine T790M was detected in all 14.

Husain’s group also found that T790M could be identified before radiographic progression of disease. Twenty-four patients treated with erlotinib were monitored for acquisition of the T790M mutation through the use of urinary ctDNA collected every 3 to 6 weeks. “T790M mutation was detected as early as 3 months prior to radiological progression,” the investigators found.

Future studies should characterize the therapeutic implications of earlier intervention with second-line therapy in patients who have early acquisition detected through the use of the urine assay, Husain advised.

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